Role of hepatitis B virus genetic barrier in drug-resistance and immune-escape development

Dig Liver Dis. 2011 Dec;43(12):975-83. doi: 10.1016/j.dld.2011.07.002. Epub 2011 Aug 9.


Background: Impact of hepatitis B virus genetic barrier, defined as the number and type of nucleotide substitutions required to overcome drug/immune selective pressure, on drug-resistance/immune-escape development is unknown.

Methods: Genetic barrier was calculated according to Van de Vijver (2006) in 3482 hepatitis B virus-reverse transcriptase/HBV surface antigen sequences from 555 drug-naïve patients and 2927 antiviral-treated patients infected with hepatitis B virus genotypes A-G.

Results: Despite high natural variability, genetic barrier for drug-resistance development is identical amongst hepatitis B virus genotypes, but varies according to drug-resistance mutation type. Highest genetic barrier is found for secondary/compensatory mutations (e.g. rtL80I/V-rtL180M-rtV173L), whilst most primary mutations (including rtM204V-rtA181T/V-rtI169T-rtA194T) are associated with low genetic barrier. An exception is rtM204I, which can derive from a transition or a transversion. Genotypes A and G are more prone to develop immune/diagnostic-escape mutations sT114R and sG130N. Vaccine-escape associated sT131N-mutation is a natural polymorphism in both A and G genotypes.

Conclusion: Genetic barrier and reverse transcriptase/HBV surface antigen overlapping can synergistically influence hepatitis B virus drug-resistance/immune-escape development. The different immune-escape potential of specific hepatitis B virus genotypes could have important clinical consequences in terms of disease progression, vaccine strategies and correct HBV surface antigen detection.

MeSH terms

  • Amino Acids / genetics
  • Codon / genetics
  • Drug Resistance, Viral / genetics*
  • Genotype*
  • Hepatitis B / drug therapy
  • Hepatitis B / immunology
  • Hepatitis B Surface Antigens / genetics*
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / immunology*
  • Humans
  • Mutation
  • Polymorphism, Genetic
  • RNA-Directed DNA Polymerase / genetics*
  • Statistics, Nonparametric
  • Treatment Failure


  • Amino Acids
  • Codon
  • Hepatitis B Surface Antigens
  • RNA-Directed DNA Polymerase